Amygdala Subregions Research Articles

Aberrant functional and causal connectivity of the amygdala in herpes zoster and post-herpetic neuralgia patients.

Resting-state functional magnetic resonance imaging (rs-fMRI) and Granger causality analysis (GCA) were used to observe the characteristics of amygdala and whole-brain effect connections in patients with herpes zoster (HZ) and post-herpetic neuralgia (PHN) and to determine their relationship with clinical features. Rs-fMRI scans were performed on 50 HZ; 50 PHN; and 50 age-, sex- and education-year-matched healthy controls (HCs). Bilateral amygdala subregions were used as seeds for functional connectivity (FC). GCA was used to analyze the effective connection of brain regions that were significantly different among groups. Then, the correlation between FC, and GCA values and clinical indices was investigated. PHN had impaired FC between the amygdala subregion with the putamen, cortex, anterior cingulate cortex (ACC) to HCs and reduced FC of medial amygdala (MeA) with the parieto-occipital lobe and motor cortex to HZ; HZ had reduced FC of the lateral amygdala (LA) with the insula to HCs. GCA values from the bilateral LA to the bilateral ACC, left MeA to the bilateral ACC and left putamen, and right ACC to the bilateral MeA were reduced in PHN patients compared to HCs. Compared with HCs, the GCA values from the left MeA to the left ACC and right putamen were reduced in HZ. The GCA values from the amygdala subregion to the ACC were positively correlated with HAMA or HAMD scores in PHN. PHN showed reduced FC between the amygdala subregions and cortico-putamen and decreased effective connectivity from the amygdala subregion to the ACC and putamen. HZ and PHN patients had significant changes in effective connectivity in brain regions, including diverse functional areas emanating from and projecting to the amygdala. The current findings will provide a new perspective for understanding the neuropathophysiological mechanism HZ and PHN.

Resting-State Functional Magnetic Resonance Imaging Study on the Functional Connectivity of Amygdalar Subregions in Patients with Chronic Non-Specific Low Back Pain

Resting-State Functional Magnetic Resonance Imaging Study on the Functional Connectivity of Amygdalar Subregions in Patients with Chronic Non-Specific Low Back Pain

Abnormality of anxious behaviors and functional connectivity between the amygdala and the frontal lobe in maternally deprived monkeys.

Anxious behaviors often occur in individuals who have experienced early adversity. Anxious behaviors can bring many hazards, such as social withdrawal, eating disorders, negative self-efficacy, self-injurious thoughts and behaviors, anxiety disorders, and even depression. Abnormal behavior are is closely related to changes in corresponding circuit functions in the brain. This study investigated the relationship between brain circuits and anxious behaviors in maternal-deprived rhesus monkey animal model, which mimic early adversity in human. Twenty-five rhesus monkeys (Macaca mulatta) were grouped by two different rearing conditions: 11 normal control and mother-reared (MR) monkeys and 14 maternally deprived and peer-reared (MD) monkeys. After obtaining images of the brain areas with significant differences in maternal separation and normal control macaque function, the relationship between functional junction intensity and stereotypical behaviors was determined by correlation analysis. The correlation analysis revealed that stereotypical behaviors were negatively correlated with the coupling between the left lateral amygdala subregion and the left inferior frontal gyrus in both MD and MR macaques. This study suggests that early adversity-induced anxious behaviors are associated with changes in the strength of the amygdala-prefrontal connection. The normalization of the regions involved in the functional connection might reverse the behavioral abnormality. It provides a solid foundation for effective intervention in human early adversity. This study suggests that early adversity-induced anxious behaviors are associated with changes in the strength of the amygdala-prefrontal connection. The higher the amygdala-prefrontal connection strength, the less stereotyped behaviors exhibited by monkeys experiencing early adversity. Thus, in the future, changing the strength of the amygdala-prefrontal connection may reverse the behavioral abnormalities of individuals who experience early adversity. This study provides a solid foundation for effective intervention in humans' early adversity.

Structural and functional improvement of amygdala sub-regions in postpartum depression after acupuncture.

This study aimed to analyze the changes in structure and function in amygdala sub-regions in patients with postpartum depression (PPD) before and after acupuncture. A total of 52 patients with PPD (All-PPD group) were included in this trial, 22 of which completed 8 weeks of acupuncture treatment (Acu-PPD group). An age-matched control group of 24 healthy postpartum women (HPW) from the hospital and community were also included. Results from the 17-Hamilton Depression Scale (17-HAMD) and the Edinburgh Postnatal Depression Scale (EPDS) were evaluated, and resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed at baseline and after the acupuncture treatment. Sub-regions of the amygdala were used as seed regions to measure gray matter volume (GMV) and analyzed for resting-state functional connectivity (RSFC) values separately. Finally, correlation analyses were performed on all patients with PPD to evaluate association values between the clinical scale scores, GMV, and RSFC values, while controlling for age and education. Pearson's correlation analyses were conducted to investigate the relevance between GMV and RSFC values of brain regions that differed before and after acupuncture treatment and clinical scale scores in Acu-PPD patients. The HAMD scores for Acu-PPD were reduced after acupuncture treatment (P < 0.05), suggesting the positive effects of acupuncture on depression symptoms. Structurally, the All-PPD group showed significantly decreased GMV in the left lateral part of the amygdala (lAMG.L) and the right lateral part of the amygdala (lAMG.R) compared to the HPW group (P < 0.05). In addition, the GMV of lAMG.R was marginally increased in the Acu-PPD group after acupuncture (P < 0.05). Functionally, the Acu-PPD group showed a significantly enhanced RSFC between the left medial part of the amygdala (mAMG.L) and the left vermis_6, an increased RSFC between the right medial part of the amygdala (mAMG.R) and left vermis_6, and an increased RSFC between the lAMG.R and left cerebelum_crus1 (P < 0.05). Moreover, correlation studies revealed that the GMV in the lAMG.R was significantly related to the EPDS scores in the All-PPD group (P < 0.05). Our findings demonstrated that the structure of amygdala sub-regions is impaired in patients with PPD. Acupuncture may improve depressive symptoms in patients with PPD, and the mechanism may be attributed to changes in the amygdala sub-region structure and the functional connections of brain areas linked to the processing of negative emotions. The fMRI-based technique can provide comprehensive neuroimaging evidence to visualize the central mechanism of action of acupuncture in PPD.

Automated subfield volumetric analysis of amygdala, hippocampus, and thalamic nuclei in mesial temporal lobe epilepsy

PurposeIdentifying relationships between clinical features and quantitative characteristics of the amygdala-hippocampal and thalamic subregions in mesial temporal lobe epilepsy (mTLE) may offer insights into pathophysiology and the basis for imaging prognostic markers of treatment outcome. Our aim was to ascertain different patterns of atrophy or hypertrophy in mesial temporal sclerosis (MTS) patients and their associations with post-surgical seizure outcomes. To assess this aim, this study is designed in 2 folds: (1) hemispheric changes within MTS group and (2) association with postsurgical seizure outcomes. Methods and materials27 mTLE subjects with mesial temporal sclerosis (MTS) were scanned for conventional 3D T1w MPRAGE images and T2w scans. With respect to 12 months post-surgical seizure outcomes, 15 subjects reported being seizure free (SF) and 12 reported continued seizures. Quantitative automated segmentation and cortical parcellation were performed using Freesurfer. Automatic labeling and volume estimation of hippocampal subfields, amygdala, and thalamic subnuclei were also performed. The volume ratio (VR) for each label was computed and compared between (1) between contralateral and ipsilateral MTS using Wilcoxon rank-sum test and (2) SF and not seizure free (NSF) groups using linear regression analysis. False Discovery rate (FDR) with significant level of 0.05 were used in both analyses to correct for multiple comparisons. ResultsAmygdala: The medial nucleus of the amygdala was the most significantly reduced in patients with continued seizures when compared to patients who remained seizure free. Hippocampus: Comparison of ipsilateral and contralateral volumes with seizure outcomes showed volume loss was most evident in the mesial hippocampal regions such as CA4 and hippocampal fissure. Volume loss was also most explicit in the presubiculum body in patients with continued seizures at the time of their follow-up. Ipsilateral MTS compared to contralateral MTS analysis showed the heads of the ipsilateral subiculum, presubiculum, parasubiculum, dentate gyrus, CA4, and CA3 were more significantly affected than their respective bodies. Volume loss was most noted in mesial hippocampal regions. Thalamus: VPL and PuL were the most significantly reduced thalamic nuclei in NSF patients. In all statistically significant areas, volume reduction was observed in the NSF group. No significant volume reductions were noted in the thalamus and amygdala when comparing ipsilateral to contralateral sides in mTLE subjects. ConclusionsVarying degrees of volume loss were demonstrated in the hippocampus, thalamus, and amygdala subregions of MTS, especially between patients who remained seizure-free and those who did not. The results obtained can be used to further understand mTLE pathophysiology. Clinical relevance/applicationIn the future, we hope these results can be used to deepen the understanding of mTLE pathophysiology, leading to improved patient outcomes and treatments.

Increased functional connectivity of amygdala subregions in patients with drug-naïve panic disorder and without comorbidities.

Amygdala plays an important role in the neurobiological basis of panic disorder (PD), and the amygdala contains different subregions, which may play different roles in PD. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the amygdala subregions in PD using resting-state functional magnetic resonance imaging and to explore the relationship between the abnormal spontaneous functional connectivity patterns of the regions of interest (ROIs) and the clinical symptoms of PD patients. Fifty-three drug-naïve, non-comorbid PD patients and 70 healthy controls (HCs) were recruited. Seed-based resting-state functional connectivity (rsFC) analyses were conducted using the bilateral amygdalae and its subregions as the ROI seed. Two samples t test was performed for the seed-based Fisher's z -transformed correlation maps. The relationship between the abnormal spontaneous functional connectivity patterns of the ROIs and the clinical symptoms of PD patients was investigated by Pearson correlation analysis. PD patients showed increased rsFC of the bilateral amygdalae and almost all the amygdala subregions with the precuneus/posterior cingulate gyrus compared with the HC group (left amygdala [lAMY]: t = 4.84, P <0.001; right amygdala [rAMY]: t = 4.55, P <0.001; left centromedial amygdala [lCMA]: t = 3.87, P <0.001; right centromedial amygdala [rCMA]: t = 3.82, P = 0.002; left laterobasal amygdala [lBLA]: t = 4.33, P <0.001; right laterobasal amygdala [rBLA]: t = 4.97, P <0.001; left superficial amygdala [lSFA]: t = 3.26, P = 0.006). The rsFC of the lBLA with the left angular gyrus/inferior parietal lobule remarkably increased in the PD group ( t = 3.70, P = 0.003). And most of the altered rsFCs were located in the default mode network (DMN). A significant positive correlation was observed between the severity of anxiety and the rsFC between the lSFA and the left precuneus in PD patients ( r = 0.285, P = 0.039). Our research suggested that the increased rsFC of amygdala subregions with DMN plays an important role in the pathogenesis of PD. Future studies may further explore whether the rsFC of amygdala subregions, especially with the regions in DMN, can be used as a biological marker of PD.

Effects of acute stress and depression on functional connectivity between prefrontal cortex and the amygdala.

Stress is known to be a significant risk factor for the development of Major Depressive Disorder (MDD), yet the neural mechanisms that underlie this risk are poorly understood. Prior work has heavily implicated the corticolimbic system in the pathophysiology of MDD. In particular, the prefrontal cortex (PFC) and amygdala play a central role in regulating the response to stress, with dorsal PFC and ventral PFC exhibiting reciprocal excitatory and inhibitory influences on amygdala subregions. However, it remains unclear how best to disentangle the impact of stress from the impact of current MDD symptoms on this system. Here, we examined stress-induced changes in resting state functional connectivity (rsFC) within an a priori corticolimbic network in MDD patients and healthy controls (total n = 80) before and after an acute stressor or a "no stress" control condition. Using graph theoretic analysis, we found that connectivity between basolateral amygdala and dorsal prefrontal nodes of the corticolimbic network had a negative association with individual differences in chronic perceived stress at baseline. Following the acute stressor, healthy individuals showed a reduction of the amygdala node strength, while MDD patients exhibited little change. Finally, dorsal PFC-particularly dorsomedial PFC- connectivity to the basolateral amygdala was associated with the strength of the basolateral amygdala responses to loss feedback during a reinforcement learning task. These findings highlight attenuated connectivity between basolateral amygdala and prefrontal cortex in patients with MDD. In healthy individuals, acute stress exposure was found to push the corticolimbic network to a "stress-phenotype" that may be chronically present in patients with current depression and high levels of perceived stress. In sum, these results help to identify circuit mechanisms underlying the effects of acute stress and their role in mood disorders.

Ethanol-Induced Suppression of G Protein–Gated Inwardly Rectifying K+–Dependent Signaling in the Basal Amygdala

BackgroundThe basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder. The GABABR (gamma-aminobutyric acid B receptor) is a promising therapeutic target for alcohol use disorder, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABABR-dependent signaling. The effect of ethanol on GABABR-dependent signaling in the BLA is unknown. MethodsGABABR-dependent signaling in the mouse BLA was examined using slice electrophysiology following repeated ethanol exposure. Neuron-specific viral genetic manipulations were then used to understand the relevance of ethanol-induced neuroadaptations in the basal amygdala subregion (BA) to mood-related behavior. ResultsThe somatodendritic inhibitory effect of GABABR activation on principal neurons in the basal but not the lateral subregion of the BLA was diminished following ethanol exposure. This adaptation was attributable to the suppression of GIRK (G protein–gated inwardly rectifying K+) channel activity and was mirrored by a redistribution of GABABR and GIRK channels from the surface membrane to internal sites. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 is necessary for the ethanol-induced neuroadaptation. Viral suppression of GIRK channel activity in BA principal neurons from ethanol-naïve mice recapitulated some mood-related behaviors observed in C57BL/6J mice during ethanol withdrawal. ConclusionsThe ethanol-induced suppression of GIRK-dependent signaling in BA principal neurons contributes to some of the mood-related behaviors associated with ethanol withdrawal in mice. Approaches designed to prevent this neuroadaptation and/or strengthen GIRK-dependent signaling may prove useful for the treatment of alcohol use disorder.

Regulation of dendritic spines in the amygdala following sleep deprivation.

The amygdala is a hub of emotional circuits involved in the regulation of cognitive and emotional behaviors and its critically involved in emotional reactivity, stress regulation, and fear memory. Growing evidence suggests that the amygdala plays a key role in the consolidation of emotional memories during sleep. Neuroimaging studies demonstrated that the amygdala is selectively and highly activated during rapid eye movement sleep (REM) and sleep deprivation induces emotional instability and dysregulation of the emotional learning process. Regulation of dendritic spines during sleep represents a morphological correlate of memory consolidation. Several studies indicate that dendritic spines are remodeled during sleep, with evidence for broad synaptic downscaling and selective synaptic upscaling in several cortical areas and the hippocampus. Currently, there is a lack of information regarding the regulation of dendritic spines in the amygdala during sleep. In the present work, we investigated the effect of 5 h of sleep deprivation on dendritic spines in the mouse amygdala. Our data demonstrate that sleep deprivation results in differential dendritic spine changes depending on both the amygdala subregions and the morphological subtypes of dendritic spines. We observed decreased density of mushroom spines in the basolateral amygdala of sleep deprived mice, together with increased neck length and decreased surface area and volume. In contrast, we observed greater densities of stubby spines in sleep deprived mice in the central amygdala, indicating that downscaling selectively occurs in this spine type. Greater neck diameters for thin spines in the lateral and basolateral nuclei of sleep deprived mice, and decreases in surface area and volume for mushroom spines in the basolateral amygdala compared to increases in the cental amygdala provide further support for spine type-selective synaptic downscaling in these areas during sleep. Our findings suggest that sleep promotes synaptic upscaling of mushroom spines in the basolateral amygdala, and downscaling of selective spine types in the lateral and central amygdala. In addition, we observed decreased density of phosphorylated cofilin immunoreactive and growth hormone immunoreactive cells in the amygdala of sleep deprived mice, providing further support for upscaling of dendritic spines during sleep. Overall, our findings point to region-and spine type-specific changes in dendritic spines during sleep in the amygdala, which may contribute to consolidation of emotional memories during sleep.

The impact of social defeat on basomedial amygdala neuronal activity in adult male rats

Social stressors negatively impact social function, and this is mediated by the amygdala across species. Social defeat stress is an ethologically relevant social stressor in adult male rats that increases social avoidance, anhedonia, and anxiety-like behaviors. While amygdala manipulations can mitigate the negative effects of social stressors, the impact of social defeat on the basomedial subregion of the amygdala is relatively unclear. Understanding the role of the basomedial amygdala may be especially important, as prior work has demonstrated that it drives physiological responses to stress, including heart-rate related responses to social novelty. In the present study, we quantified the impact of social defeat on social behavior and basomedial amygdala neuronal responses using anesthetized in vivo extracellular electrophysiology in adult male Sprague Dawley rats. Socially defeated rats displayed increased social avoidance behavior towards novel Sprague Dawley conspecifics and reduced time initiating social interactions relative to controls. This effect was most pronounced in rats that displayed defensive, boxing behavior during social defeat sessions. We next found that socially defeated rats showed lower overall basomedial amygdala firing and altered the distribution of neuronal responses relative to the control condition. We separated neurons into low and high Hz firing groups, and neuronal firing was reduced in both low and high Hz groups but in a slightly different manner. This work demonstrates that basomedial amygdala activity is sensitive to social stress, displaying a distinct pattern of social stress-driven activity relative to other amygdala subregions.

Epigenetic aging and PTSD outcomes in the immediate aftermath of trauma.

Psychological trauma exposure and posttraumatic stress disorder (PTSD) have been associated with advanced epigenetic age. However, whether epigenetic aging measured at the time of trauma predicts the subsequent development of PTSD outcomes is unknown. Moreover, the neural substrates underlying posttraumatic outcomes associated with epigenetic aging are unclear. We examined a multi-ancestry cohort of women and men (n = 289) who presented to the emergency department (ED) after trauma. Blood DNA was collected at ED presentation, and EPIC DNA methylation arrays were used to assess four widely used metrics of epigenetic aging (HorvathAge, HannumAge, PhenoAge, and GrimAge). PTSD symptoms were evaluated longitudinally at the time of ED presentation and over the ensuing 6 months. Structural and functional neuroimaging was performed 2 weeks after trauma. After covariate adjustment and correction for multiple comparisons, advanced ED GrimAge predicted increased risk for 6-month probable PTSD diagnosis. Secondary analyses suggested that the prediction of PTSD by GrimAge was driven by worse trajectories for intrusive memories and nightmares. Advanced ED GrimAge was also associated with reduced volume of the whole amygdala and specific amygdala subregions, including the cortico-amygdaloid transition and the cortical and accessory basal nuclei. Our findings shed new light on the relation between biological aging and trauma-related phenotypes, suggesting that GrimAge measured at the time of trauma predicts PTSD trajectories and is associated with relevant brain alterations. Furthering these findings has the potential to enhance early prevention and treatment of posttraumatic psychiatric sequelae.

Regional superficial amygdala resting-state functional connectivity in adults infers childhood maltreatment severity.

Childhood maltreatment (CM) is a potential risk factor for some neuropsychiatric disorders in adulthood (e.g. depression and anxiety) and alters trajectories of brain development. Accumulating evidence suggests that functional connectivity of the limbic system, especially the amygdala, is highly associated with childhood maltreatment, although not all studies have found this. These inconsistent results may be due to differential alterations of amygdala resting-state functional connectivity (rsFC) following childhood maltreatment. Our aim was to investigate the relationship between the rsFC of amygdala subregions and CM severity, as well as to develop a stable rsFC-based model for inferring the severity of CM. In this study, we employed the Childhood Trauma Questionnaire (CTQ) to assess CM severity in each individual. We explored the relationship between the rsFC of amygdala subregions (i.e. centromedial -CMA, basolateral -BLA, superficial-SFA amygdala) and CM experience in a discovery dataset of n=110 healthy Chinese participants by linear multiple regression analysis. Subsequent dimensional and categorical approach were performed to elucidate the relationship between rsFCs and CM severity and CM subtypes, respectively. A support vector regression model was then conducted to validate the associations between rsFCs and total CTQ scores. Moreover, we also verified the model into another independent replication dataset (n=38). Our findings suggested that childhood maltreatment was negatively associated with rsFC between the right superficial amygdala and perigenual anterior cingulate cortex (pgACC)/postcentral gyrus (PCG) but not the other two amygdala subregions. Moreover, SFA-pgACC coupling was more associated with physical neglect whereas the SFA-PCG was more related to emotional neglect. In addition, supervised machine learning confirmed that using these two rsFCs as predictors could stably estimate continuous maltreatment severity in both discovery and replication datasets. The current study supports that the rsFCs of superficial amygdala are related to childhood maltreatment and which may be a potential biomarker for the effects of childhood maltreatment-related psychiatric disorders (i.e. depression and anxiety).

Unbalanced amygdala communication in major depressive disorder

BackgroundPrevious studies suggested an association between functional alteration of the amygdala and typical major depressive disorder (MDD) symptoms. Examining whether and how the interaction between the amygdala and regions/functional networks is altered in patients with MDD is important for understanding its neural basis. MethodsResting-state functional magnetic resonance imaging data were recorded from 67 patients with MDD and 74 age- and sex-matched healthy controls (HCs). A framework for large-scale network analysis based on seed mappings of amygdala sub-regions, using a multi-connectivity-indicator strategy (cross-correlation, total interdependencies (TI), Granger causality (GC), and machine learning), was employed. Multiple indicators were compared between the two groups. The altered indicators were ranked in a supporting-vector machine-based procedure and associated with the Hamilton Rating Scale for Depression scores. ResultsThe amygdala connectivity with the default mode network and ventral attention network regions was enhanced and that with the somatomotor network, dorsal frontoparietal network, and putamen regions in patients with MDD was reduced. The machine learning analysis highlighted altered indicators that were most conducive to the classification between the two groups. LimitationsMost patients with MDD received different pharmacological treatments. It is difficult to illustrate the medication state's effect on the alteration model because of its complex situation. ConclusionThe results indicate an unbalanced interaction model between the amygdala and functional networks and regions essential for various emotional and cognitive functions. The model can help explain potential aberrancy in the neural mechanisms that underlie the functional impairments observed across various domains in patients with MDD.

Common and distinct roles of amygdala subregional functional connectivity in non-motor symptoms of Parkinson’s disease

Neuroimaging studies suggest a pivotal role of amygdala dysfunction in non-motor symptoms (NMS) of Parkinson’s disease (PD). However, the relationship between amygdala subregions (the centromedial (CMA), basolateral (BLA) and superficial amygdala (SFA)) and NMS has not been delineated. We used resting-state functional MRI to examine the PD-related alterations in functional connectivity for amygdala subregions. The left three subregions and right BLA exhibited between-group differences, and were commonly hypo-connected with the frontal, temporal, insular cortex, and putamen in PD. Each subregion displayed distinct hypoconnectivity with the limbic systems. Partial least-squares analysis revealed distinct amygdala subregional involvement in diverse NMS. Hypo-connectivity of all four subregions was associated with emotion, pain, olfaction, and cognition. Hypo-connectivity of the left SFA was associated with sleepiness. Our findings highlight the hypofunction of the amygdala subregions in PD and their preliminary associations with NMS, providing new insights into the pathogenesis of NMS.

Amygdala dismantled: the role of amygdala subregions in epilepsy.

This scientific commentary refers to: 'Amygdala subnuclear volumes in temporal lobe epilepsy with hippocampal sclerosis and in non-lesional patients' by Ballerini et al. (https://doi.org/10.1093/braincomms/fcac225).

Effects of footshock stress on social behavior and neuronal activation in the medial prefrontal cortex and amygdala of male and female mice.

Social behavior is complex and fundamental, and its deficits are common pathological features for several psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress may have a negative impact on social behavior, and these effects can vary based on sex. The aim of this study was to explore the effect of acute footshock stress, using analogous parameters to those commonly used in fear conditioning assays, on the sociability of male and female C57BL/6J mice in a standard social approach test. Animals were divided into two main groups of footshock stress (22 male, 24 female) and context exposed control (23 male and 22 female). Each group had mice that were treated intraperitoneally with either the benzodiazepine-alprazolam (control: 10 male, 10 female; stress: 11 male, 11 female), or vehicle (control: 13 male, 12 female; stress: 11 male, 13 female). In all groups, neuronal activation during social approach was assessed using immunohistochemistry against the immediate early gene product cFos. Although footshock stress did not significantly alter sociability or latency to approach a social stimulus, it did increase defensive tail-rattling behavior specifically in males (p = 0.0022). This stress-induced increase in tail-rattling was alleviated by alprazolam (p = 0.03), yet alprazolam had no effect on female tail-rattling behavior in the stress group. Alprazolam lowered cFos expression in the medial prefrontal cortex (p = 0.001 infralimbic area, p = 0.02 prelimbic area), and social approach induced sex-dependent differences in cFos activation in the ventromedial intercalated cell clusters (p = 0.04). Social approach following stress-induced cFos expression was positively correlated with latency to approach and negatively correlated with sociability in the prelimbic area and multiple amygdala subregions (all p < 0.05). Collectively, our results suggest that acute footshock stress induces sex-dependent alterations in defensiveness and differential patterns of cFos activation during social approach.

Exercise reduces the anxiogenic effects of meta-chlorophenylpiperazine: The role of 5-HT2C receptors in the bed nucleus of the stria terminalis.

Two weeks of voluntary exercise in group-housed mice produces a reduction in anxiety-like behaviors across a number of different measures, including a reduction in the anxiety levels typically produced by the anxiogenic serotonergic drug m-chlorophenylpiperazine (mCPP), an agonist at 5-HT2C/2b receptors. We have previously demonstrated that 2-weeks of voluntary exercise blunted the anxiogenic effects of systemic mCPP, and we have also shown that mCPP infused into the bed nucleus of the stria terminalis (BNST) is anxiogenic. Here we follow up on these reports. In Experiment 1 we infused several doses of mCPP into the BNST with or without the 5-HT2C antagonist SB242084. In Experiment 2, we administered mCPP into amygdala subregions and the dorsal hippocampus to investigate site specificity. In Experiment 4 we lesioned the BNST and subsequently infused mCPP systemically, and in Experiment 4 we used RNAscope® to assess BNST 5-HT2C transcripts following wheel running. BNST mCPP infusion increased acoustic startle responding, which was by 5-HT2C antagonism, while neither mCPP infused into the amygdala nor hippocampus was anxiogenic. Lesions of the BNST prevented the anxiogenic effect of systemically administered mCPP. Lastly, exercise reduced 5-HT2C transcripts in the BNST. These results suggest that the BNST is a critical site of action for the effects of exercise on mCPP. Together these data suggest that exercise may reduce 5-HT2C receptor function in the BNST, which may, in part, explain some of the anxiolytic effects associated with wheel running.

Structural covariance network of the hippocampus-amygdala complex in medication-naïve patients with first-episode major depressive disorder.

The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder (MDD). Each of these structures consists of several heterogeneous subfields. We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus-amygdala complex in medication-naïve patients with first-episode MDD. High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode, medication-naïve, and noncomorbid MDD patients and 81 age-, sex-, and education level-matched healthy control participants (HCs). The structural covariance network (SCN) was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions; the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions, controlled for age, sex, education level, and intracranial volume. The global and nodal graph metrics were calculated and compared between groups. Compared with HCs, the SCN within the hippocampus-amygdala complex in patients with MDD showed a shortened mean characteristic path length, reduced modularity, and reduced small-worldness index. At the nodal level, the left hippocampal tail showed increased measures of centrality, segregation, and integration, while nodes in the left amygdala showed decreased measures of centrality, segregation, and integration in patients with MDD compared with HCs. Our results provide the first evidence of atypical topologic characteristics within the hippocampus-amygdala complex in patients with MDD using structure network analysis. It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.

Disorganized functional architecture of amygdala subregional networks in obsessive-compulsive disorder

A precise understanding of amygdala-centered subtle networks may help refine neurocircuitry models of obsessive-compulsive disorder (OCD). We applied connectivity-based parcellation methodology to segment the amygdala based on resting-state fMRI data of 92 medication-free OCD patients without comorbidity and 90 matched healthy controls (HC). The amygdala was parcellated into two subregions corresponding to basolateral amygdala (BLA) and centromedial amygdala (CMA). Amygdala subregional functional connectivity (FC) maps were generated and group differences were evaluated with diagnosis-by-subregion flexible factorial ANOVA. We found significant diagnosis × subregion FC interactions in insula, supplementary motor area (SMA), midcingulate cortex (MCC), superior temporal gyrus (STG) and postcentral gyrus (PCG). In HC, the BLA demonstrated stronger connectivity with above regions compared to CMA, whereas in OCD, the connectivity pattern reversed to stronger CMA connectivity comparing to BLA. Relative to HC, OCD patients exhibited hypoconnectivity between left BLA and left insula, and hyperconnectivity between right CMA and SMA, MCC, insula, STG, and PCG. Moreover, OCD patients showed reduced volume of left BLA and right CMA compared to HC. Our findings characterized disorganized functional architecture of amygdala subregional networks in accordance with structural defects, providing direct evidence regarding the specific role of amygdala subregions in the neurocircuitry models of OCD.

Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors.

The hippocampus and the amygdala play a central role in post-traumatic stress disorder (PTSD) pathogenesis. While alternations in volumes of both regions have been consistently observed in individuals with PTSD, it remains unknown whether these reflect pre-trauma vulnerability traits or acquired post-trauma consequences of the disorder. Here, we conducted a longitudinal panel study of adult civilian trauma survivors admitted to a general hospital emergency department (ED). One hundred eligible participants (mean age = 32.97 ± 10.97, n = 56 females) completed both clinical interviews and structural MRI scans at 1-, 6-, and 14-months after ED admission (alias T1, T2, and T3). While all participants met PTSD diagnosis at T1, only n = 29 still met PTSD diagnosis at T3 (a "non-Remission" Group), while n = 71 did not (a "Remission" Group). Bayesian multilevel modeling analysis showed robust evidence for smaller right hippocampus volume (P+ of ~0.014) and moderate evidence for larger left amygdala volume (P+ of ~0.870) at T1 in the "non-Remission" group, compared to the "Remission" group. Subregion analysis further demonstrated robust evidence for smaller volume in the subiculum and right CA1 hippocampal subregions (P+ of ~0.021-0.046) in the "non-Remission" group. No time-dependent volumetric changes (T1 to T2 to T3) were observed across all participants or between groups. Results support the "vulnerability trait" hypothesis, suggesting that lower initial volumes of specific hippocampus subregions are associated with non-remitting PTSD. The stable volume of all hippocampal and amygdala subregions does not support the idea of consequential, progressive, stress-related atrophy during the first critical year following trauma exposure.